53

Atherosclerosis, 83 (1990) 53-58 Elsevier Scientific Publishers Ireland, Ltd.

ATHERO

04489

Effect of lovastatin on hemorheology in type II hyperlipoproteinemia R. Koppensteiner, Division of Angiology, First Department

E. Minar and H. Ehringer of Medicine, University of Vienna, Vienna (Austria)

(Received 23 October, 1989) (Revised, received 2 March, 1990) (Accepted 9 March, 1990)

To assess the effect of lovastatin on blood rheology, the hemorheological determinants fibrinogen, red cell aggregation, plasma viscosity, hematocrit and platelet aggregation (spontaneous and ADP-induced) were studied in 15 patients with type II hyperlipoproteinemia in the course of treatment with lovastatin. Prior to therapy, fibrinogen (Fgen), red cell aggregation (RCA-S, RCA-L) and plasma viscosity (PV) as well as cholesterol (Chol) and triglycerides (Tg) were increased in the hyperlipemic patients compared with healthy normolipemic controls (Fgen: 319.3 k 65 vs. 269.8 + 48 mg/dl; RCA-S: 7.93 f 1 vs. 6.62 f 1, RCA-L: 9.86 f 1 vs. 7.8 + 1 arbitrary units; PV: 1.75 vs. 1.63 mPa/s; Chol: 317.0 + 32 vs. 176.5 + 21 mg/dl; Tg: 154.5 + 88 vs. 72.8 f 16 mg/dl; all P c: 0.05). Three months of treatment with lovastatin resulted in a marked decrease in red cell aggregation and plasma viscosity, parallel to a fall in cholesterol (the following pretreatment values were monitored after a standard lipid-lowering diet; RCA-S: 7.59 + 1 vs. 6.65 k 0.9, RCA-L: 9.34 k 1 vs. 8.15 k 1 arbitrary units; PV: 1.74 vs. 1.65 mPa/s; Chol: 309.8 f 41 vs. 217.1 k 30 mg/dl; all P < 0.01); fibrinogen however, remained unchanged throughout the treatment period (346.4 + 73.3 vs. 330.5 + 70.2 mg/dl, n.s.). No differences were seen in hematocrit and platelet aggregability between hyperlipemic patients and controls and no changes occurred in these parameters during the study. Our data suggest that treatment with lovastatin improves blood rheology in patients with type II hyperlipoproteinemia by lowering abnormally raised plasma viscosity and red cell aggregation; these effects are most likely due to the decrease in cholesterol as fibrinogen remained unaffected by lovastatin therapy.

Key words: Hyperlipoproteinemia,

type II; Fibrinogen;

Red cell aggregation;

Plasma viscosity

Introduction Correspondence to: Dr. R. Koppensteiner, Division Angiology, First Department of Medicine, University Vienna, Lazarettgasse 14, A-1090 Vienna, Austria.

0021-9150/90/$03.50

0 1990 Elsevier Scientific

of of

Increased blood and plasma viscosity have been frequently reported in patients with primary hy-

Publishers Ireland, Ltd.

54 perlipoproteinemia [l-6] and attributed to increased plasma lipoprotein concentrations [l-3,7] and elevated fibrinogen levels [3-5.71. Hyperlipoproteinemic patients may benefit from treatment with lipid-lowering agents that also affect blood rheology. Clofibrate is one of the drugs with the favorable effect of decreasing plasma fibrinogen and has been shown to reduce blood and plasma viscosity in hyperlipemic patients with manifest atherosclerotic disease ]5,6$]. Patients on clofibrate treatment showed clinical improvement possibly related to improving blood flow due to changing hemorheological conditions [5]. Treatment with gemfibrozil, another fibric acid derivate, also resulted in a reduction of fibrinogen, most likely caused by a fibrinolytic action of the drug 191. Lovastatin, a HMG-CoA-reductase inhibitor, is a recently introduced lipid-lowering agent with a high efficacy in reducing cholesterol [lO,ll]. However, data about its potential hemorheological effects have not been available so far. Thus, the aim of our study was to assess the effect of lovastatin on blood rheology by evaluating various hemorheological parameters in patients with type II hyperlipoproteinemia in the course of treatment with lovastatin. The questions of whether lovastatin, due to its high efficacy in reducing cholesterol, produces changes in hemorheological parameters of similar degree, and, whether lovastatin affects plasma fibrinogen as a major determinant of blood rheol__.I XII_.._ Xrl vg,r WeIs, p”“.W;~‘ ~*Lulllllru. Patients and methods Fifteen patients (5 males, 10 females; age 58.8 + 9 years, mean + SD) with primary type II hyperlipoproteinemia (10 type IIa, 5 type IIb) were studied. Secondary hyperlipoproteinemia was excluded by laboratory tests. Manifestations of peripheral arterial occlusive disease were present in 11 patients (clinical stage IIa disease according to Fontaine); 5 patients had evidence of coronary heart disease with a history of angina pectoris, 2 patients had carotid stenoses of more than 50% as evaluated by a high resolution ultrasound real-time duplex system; all patients were free of acute cardiovascular and cerebrovascular symptoms.

Three patients were hypertensive with an ongoing need for antihypertensive drugs (nifedipine, clonidine), and 4 patients smoked a maximum of one pack of cigarettes a day. No patient was on a lipid-lowering diet or took drugs known to affect lipid metabolism prior to the study, and none was taking hemorheologically active drugs before and throughout the study. Platelet aggregation inhibitors were stopped at least 2 weeks before the patients entered the study. Other additional medication (nifedipine, clonidine, isosorbitdinitrate, methyldigoxine) was held constant during the period of investigation. All patients had normal weight according to the Broca-Index. Fifteen ageand sex-matched clinically healthy normolipemic subjects without any evidence of metabolic, neoplastic or inflammatory disease were used as controls. All patients started a standard lipid-lowering diet (diet recommended by the American Heart Association) for a minimum of 2 months. Only patients with fasting piasma cholesterol above 250 mg/dl after the dietary phase entered a 4-week placebo baseline period, followed by a 12-week active treatment period. The initial dose of lovastatin was one tablet daily (20 mg; to be taken with the evening meal) in patients with a total cholesterol of less than 300 mg/dl, 40 mg/day when cholesterol exceeded 300 mg/dl. After 4 weeks of treatment the dose was increased to 80 mg/day if cholesterol still exceeded 250 mg/dl. Hemorheological parameters were monitored at the Cllr

lwn;nn;nn “c~unu”~

nf “I

the Ll‘r

A;nt.anr UIs,CUIJ

mh.aca ~“Uc.~,

ot UI

tha L,,ti

hmGn_ vyju-

ning of the placebo baseline phase and then at the beginning and end of the 12-week active treatment period. Patients attended the clinic in the morning, having fasted for at least 12 h. Blood was collected from the antecubital vein for immediate determination of the following rheological parameters: fibrinogen (Fgen, mg/dl): Clauss [12]; plasma viscosity (PV, mPa/s): Coulter-Harkness capillary viscometer, 25 o C [13]; red cell aggregation (RCA, arbitrary units): MAl-aggregometer, Myrenne [14]; heparinized blood, 10 U/ml, adjusted to a standard hematocrit of 45%, (a) in stasis (after rotation stop): RCA-S, (b) at low shear (3/s): RCA-L; platelet aggregation (PA, %): PA2_aggregometer, Myrenne [15]; titrated blood, 3.8%, 1 : 10; PRP, corrected platelet count 250 x

55 109/1, constant shear rate 40/s. (a) spontaneous (PA sp), (b) ADP-induced (PA ADP): final concentration 5 x lo-’ mol/l; hematocrit (Hc, 4%): microhematocrit [16]. Simultaneously, blood was drawn for routine hematologic and chemistry profiles, including plasma cholesterol (Chol) and triglycerides (Tg) (enzymatically, Boehringer assay, Boehringer Marmheim). Blood pressure and body weight were measured at each visit. Results are given as means and standard deviation. The t-test for unpaired data was used to compare the hyperlipemic patients with the controls. Changes in the course of treatment were studied by analysis of variance and Tukey’s studentized range test. Coefficients of correlation were calculated according to Pearson.

Results Prior to the study, patients with primary hyperlipoproteinemia had higher cholesterol, triglycerides, fibrinogen, red cell aggregation and plasma viscosity than healthy normolipemic controls (Table 1).

TABLE

1

RHEOLOGICAL DATA AND PLASMA LIPOPROTEINS IN PATIENTS WITH TYPE II HYPERLIPOPROTEINEMIA COMPARED WITH HEALTHY CONTROLS Values are means + SD. Chol = cholesterol; Tg = triglycerides; HDL = high density lipoproteins; Fgen = fibrinogen; RCA-S = red cell aggregation in stasis; RCA-L = red cell aggregation at low shear; Hc = hematocrit; PV = plasma viscosity; PA sp and PA ADP = spontaneous and ADP-induced platelet aggregation; a.“. = arbitrary units. Controls (n =15)

P

Discussion

(n=15) 317.06 f 32.54 154.53 f 88.37 56.40&11.66 319.33 f 65.46 7.93* 1.39 9.86* 1.87 44.42k 4.25 1.75* 0.07 12.37 f 5.28 74.12 f 7.84

176.53 + 21.71 72.86 f 16.08 56.46+11.20 269.85 f 48.58 6.62+ 1.64 7.80f 1.61 44.93* 3.59 1.63zt 0.04 14.13+ 17.69 72.33 + 15.67

-=c 0.01 < 0.01 n.s. < 0.01 < 0.05 < 0.01 n.s. < 0.01 n.s. n.s.

The etiological role of hypercholesterolemia in atherogenesis and as a risk factor for coronary heart disease is well established [17,18]. According to Ross and Harker [19], chronic hyperlipidemia may cause the primary endothelial injury that initiates the process of atherosclerosis. Lovastatin, a HMG-CoA reductase inhibitor, is expected to further decrease the risk of coronary heart disease in hyperlipemic patients due to its high efficacy in

Patients Chol (mg/dl) Tg (mg/dl) HDL (mg/dl) Fgen (mg/dl) RCA-S (a.u.) RCA-L (a.u.) Hc (X) PV (mPa/s) PA SP (s) PA ADP (5)

In the whole population, both cholesterol and triglycerides were correlated with fibrinogen and plasma viscosity (Chol/Fgen: r = 0.38; P = 0.03; Chol/PV: r = 0.72, P = 0.001; Tg/Fgen: r = 0.45, P = 0.01; Tg/PV: r = 0.41, P = 0.02) and fibrinogen was correlated with plasma viscosity (r = 0.43, P = 0.01). Red cell aggregation was related to fibrinogen (RCA-S/Fgen: r = 0.67, P = 0.001; RCA-L/Fgen: r = 0.75, p = 0.0001) as well as to cholesterol (RCA-S/Chol: (r = 0.38, P = 0.03; RCA-L/Chol: r = 0.46, p = 0.009) and triglycerides (RCA-S/Tg: r = 0.4, P = 0.02; RCAL/Tg: r = 0.49, P = 0.005). In the 15 hyperlipemic patients, fibrinogen was related to red cell aggregation (RCA-S: r = 0.60, P = 0.01; RCA-L: r = 0.70, P = 0.003). A correlation of cholesterol, triglycerides or fibrinogen to plasma viscosity or any other rheological parameter could not be established. After the dietary phase a slight decrease was seen in cholesterol which did not reach statistical significance; there were also slight (not significant) decreases in plasma viscosity and red cell aggregation (Fig. 1, Table 2). No changes were seen in any of the parameters during the placebo baseline period. Three months of active treatment with lovastatin resulted in a reduction of cholesterol by 30%. Simultaneously, red cell aggregation, both RCA-S and RCA-L, decreased by 12 and 13%, respectively. Plasma viscosity was reduced by 6% (see Fig. 1, Table 2). Fibrinogen, platelet aggregation and hematocrit remained unchanged during treatment. There were no changes in the concomitantly monitored routine laboratory parameters as well as in blood pressure and body weight. No side effects of lovastatin therapy were observed.

56 TABLE

2

CHANGES TEINEMIA

IN RHEOLOGICAL DATA AND PLASMA BEFORE AND AFTER LIPID LOWERING

LIPOPROTEINS IN 15 PATIENTS WITH TYPE II HYPERLIPOPRODIET AND AFTER TREATMENT WITH LOVASTATIN

Values are means + SD. Chol = cholesterol; Tg = triglycerides; HDL = high density lipoproteins; Fgen = fibrinogen; RCA-S = red cell aggregation in stasis; RCA-L = red cell aggregation at low shear; Hc = hematocrit; PV = plasma viscosity; PA sp and PA ADP = spontaneous and ADP-induced platelet aggregation; au. = arbitrary units. Before treatment Chol (mg/dl) Tg (mg/dI) HDL (mg/dl) Fgen (mg/dl) RCA-S (a.u.) RCA-L (a.u.) Hc (W) PV (mPa/s) PA sp (S) PA ADP ( W) a P = level of significance

317.06 f 154.53 + 56.40+ 319.33 + 7.93+ 9.86* 44.42+ 1.75 f 12.37+ 74.12+ according

32.5 88.3 11.6 65.4 1.3 1.8 4.2 0.01 5.2 7.8 to analysis

After diet

After lovastatin

P”

309.86 f 41.9 176.26 f 124.8 55.805 15.1 346.40* 73.3 7.59* 1.0 9.34* 1.5 45.07rl_ 4.8 1.74rfI 0.09 11.42k 5.2 65.92k 17.8

217.13 + 30.2 123.73 k 72.4 63.53+ 1.3 330.57 f 70.2 6.65+ 0.9 8.15, 1.0 44.5 f 3.9 1.65rfr 0.04 15.0 k10.8 63.87& 9.9

-c 0.01 ns. ns ns. i 0.01 < 0.01 ns. < 0.01 ns. ns.

of variance.

reducing cholesterol [lO,ll]. However, abnormalities in blood rheology associated with hyperlipoproteinemia may contribute to atherosclerosis by reducing arterial blood flow, in particular at low shear conditions in the microcirculation. In our patients with type II hyperlipoproteinemia, red cell aggregation, plasma viscosity and fibrinogen were clearly elevated in comparison with normolipemic controls. The cause of hyperfibrinogenemia in hyperlipidemia, which has been previously described [4,7,8,20], is not clearly identified. Hyperfibrinogenemia may be due to a chronic-phase response described as ‘hematologic stress syndrome’ in a state of chronic disorder; in our patients it may also be related to the presence of manifestations of atherosclerosis [21]. The elevation of fibrinogen may be caused by increased hepatic synthesis stimulated by humoral mediators such as interleukins, but also by reduced fibrinolytic activity (22) indicated by increased q-antiplasmin and plasminogen (4,7). Increased red cell aggregation is most likely to result from elevated fibrinogen: fibrinogen plays a major role in rouleaux formation of red cells by acting as a ‘bridging’ macromolecule between the cells. Further, LDL and VLDL may also affect red cell aggregation due to their large molecular size [l]. Plasma viscosity may be influenced by both fibrinogen and plasma lipoproteins. Leonhardt et

al. reported an increase in plasma viscosity with raising LDL and VLDL concentrations [l]; in contrast, Lowe et al. [4] found that plasma viscosity was unrelated to plasma lipoproteins, but increased with the fibrinogen level. From our data it seems unlikely that a small reduction of cholesterol will improve hemorheology, as the decrease in red cell aggregation and plasma viscosity during the dietary phase failed to reach statistical significance. During lovastatin therapy a steep and sustained fall in cholesterol was seen which was associated with a decrease in red cell aggregation and plasma viscosity. The abnormally raised fibrinogen remained unchanged throughout the treatment period; this may be responsible for the only slight reduction of plasma viscosity (by 6%) despite marked reduction of cholesterol. In contrast, treatment with clofibrate resulted in a 16% decrease of plasma viscosity which was explained by the additive fibrinogenlowering effect of the drug [6]. As fibrinogen remained unchanged in our study, the observed effects of lovastatin on red cell aggregation and plasma viscosity must be assumed to be mediated by the fall in plasma cholesterol. Whether there are direct effects of lovastatin on red cells cannot be answered from our data. We cannot exclude that lovastatin would have caused a reduction of fibrinogen secondary to reduced lipid levels in hyperlipoproteinemic pa-

57

w

RCA-L UCA-S

initial

after

after

values

diet

lovastatin

Fig. 1. Changes in plasma cholesterol (Chol), plasma viscosity (PV) and red cell aggregation (RCA; RCA-S: in stasis; RCA-L: at low shear) in the course of lipid lowering treatment with diet and lovastatin in 15 patients with type II hyperlipoproteinemia. Values are given as means, vertical bars show standard deviations.

tients without atherosclerotic disease. However, especially patients with manifest atherosclerotic disease would benefit from a fibrinogen-lowering effect of the drug as hyperfibrinogenemia has been identified as an independent risk factor for cardiovascular events [23,24]. It is conceivable that the association between hyperlipidemia and atherosclerosis may be, to some extent, mediated through the plasma fibrinogen level. Findings concerning platelet function in hyperlipoproteinemia are controversial [4,25]. Like Lowe et al. [4] we did not see differences between untreated hyperlipemics and controls; no changes in platelet aggregability were observed in the course of lovastatin therapy with the methods applied.

We conclude that lovastatin improves blood rheology in patients with type II hyperlipoproteinemia and associated manifest atherosclerotic disease by decreasing abnormally raised red cell aggregation and plasma viscosity. These positive effects of lovastatin on hemorheology may contribute to reducing the risk of atherosclerotic disease or to retarding its progression. Long-term primary prevention trials with various lipid-lowering agents other than lovastatin demonstrated that the incidence of coronary heart disease morbidity and mortality can be diminished by reducing cholesterol [26-281; however, nothing is reported about the fibrinogen levels of the patients studied. But as lovastatin obviously does not affect increased fibrinogen levels, at least not in patients with manifest atherosclerotic disease, it has still to be established whether the risk of atherosclerotic vascular disease can be adequately controlled by reducing only cholesterol, but with hyperfibrinogenemia persisting. It has to remain open whether moderate reduction of both cholesterol and fibrinogen would provide a better prophylactic effect against initiation and progression of atherosclerosis. References Leonhardt, H., Amtz, H.R. and Klemens, U.H., Studies of plasma viscosity in primary hyperlipoproteinemia, Atherosclerosis, 28 (1977) 29. Seplowitz, A.H., Chien, S. and Smith, F.R., Effects of lipoproteins on plasma viscosity. Atherosclerosis, 38 (1981) 89. Amtz, H.R., Leonhardt, H. and Dreykluft, H.R., Influence of clofibrate on blood viscosity in primary hyperlipoproteinemia, Klin. Wochenschr., 57 (1979) 43. Lowe, G.D.O., Stromberg, P.. Forbes, C.D.. McArdle, B.M., Lorimer, A.R. and Prentice, C.R.M., Increased blood viscosity and fibrinolytic inhibitor in type II hyperlipoproteinemia. Lancet, i (1982) 472. Dormandy, J.A., Gutteridge, J.M.C., Hoare. E. and Dormandy. T.L., Effect of clofibrate on blood viscosity in intermittent claudication, Br. Med. J., 4 (1974) 259. Pfeiffer, M. and Tilsner, V., Der Einfluss von Etofibrat auf die Plasmaviskositlt bei Hyperlipoproteinamien, Med. Klin., 73 (1978) 60. Spoettl, F. and Froschauer. J., Influence of etofibrate on plasma fibrinogen and plasminogen concentrations in patients with different forms of primary hyperlipoproteinemia, Atherosclerosis, 25 (1976) 293. Cotton, R,.C. and Wade, E.G., Further observations on the effect of ethyl-a-p-chlorophenoxyisobutyrate + androsterone

58

9

10

11

12

13 14

15

16 17

18

19

(Atromid) on plasmid fibrinogen and serum cholesterol in patients with ischemic heart disease, J. Atheroscler. Res., 6 (1966) 98. Avellone, G., Di Garbo, V., Panno, A.V., Cordova, R.. Lepore, R. and Strano, A., Changes induced by gemfibrozil on lipidic, coagulative and fibrinolytic pattern in patients with type IV hyperlipoproteinemia, Intern. Ang., 7 (1988) 270. Gnmdy, MS., HMG-CoA reductase inhibitor for treatment of hypercholesterolemia , N. Engl. J. Med., 318 (1988) 24. Tobert, J.A., New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutaryl-coenzyme A reductase, Circulation, 76 (1987) 534. Clauss, A,., Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens, Acta Haematol.. 17 (1957) 235. Harkness, J.. A new instrument for the measurement of plasma viscosity, Lancet, ii (1963) 280. S&mid-Schonbein, H., Volger, E., Teitel, P., Kiesewetter. H., Dauer, U. and Heilmann, L., New hemorheological techniques for routine laboratory. Clin. Hemorheology 2 (1982) 93. Klose, H.J.. A rheological method for quantification of platelet aggregation (PA) in vitro and its kinetics under defined flow conditions, Thromb. Res., 7 (1975) 261. Deutsch, E. and Geyer, E., Laboratoriumsdiagnostik, Verlag August Steinkopf, Berlin, 1975. p. 221. Carlson, L.A. and Boettiger, L.E., Ischemic heart-disease in relation to fasting values of plasma triglycerides and cholesterol (Stockholm Prospective Study), Lancet, i (1972) 865. Kannel, W.B., Castelli, W.P., Gordon, T. and McNamara. P.M.. Serum cholesterol. lipoproteins, and the risk of coronary heart disease - The Framingham study, Ann. Intern. Med., 74 (1971) 1. Ross, R. and Harker, L., Hyperlipidemia and atherosclerosis, Science, 193 (1976) 1094.

20 Lowe, G.D.O., Drummond, M.M. and Third, J.L.H.C.. Increased plasma fibrinogen and platelet-aggregates in type II hyperlipoproteinemia. Thromb. Haemost., 42 (1979) 1053. 21 Stuart, J.. The acute-phase reaction and hematological stress syndrome in vascular disease, Int. J. Micro&c. Clin. Exp.. 3 (1984) 115. 22 Stuart, J., George. A.J., Davies. A.J.. Aukland. A., and Hurlow, R.A., Hematological stress syndrome in atherosclerosis. J. Clin. Pathol.. 34 (1981) 464. 23 Wilhelmsen, L.. Svaerdsudd. K.. Korsan-Bengtsen. K., Larsson, B.. Welin. L. and Tibblin, G., Fibrinogen as a risk factor for stroke and myocardial infarction. N. Engl. J. Med., 311 (1984) 501. 24 Meade, T.W., Brozovic, M.. Chakrabarti. R.R., Haines, A.P.. lmeson, J.D., Mellows, S.. Miller. G.J., North, W.R.S.. Stirling. Y. and Thompson, S.G.. Haemostatic function and ischemic heart disease: Principal results of the Northwick Park Heart Study, Lancet, ii (1986) 533. 25 Carvalhn, A.C.A.. Colman, R.W. and Lees, R.S., Platelet function in hyperlipoproteinemia. N. Engl. J. Med., 290 (1974) 434. 26 WHO Cooperative Trial on Primary Prevention of Ischemic Heart Disease with Clofibrate to Lower Serum Cholesterol: Final Mortality Follow-up. Report of the committee of principal investigators. Lancet. ii (1984) 600. 27 The Lipid Research Clinical Coronary Primary Prevention Trial Results, Reduction in Incidence of Coronary Heart Disease, JAMA, 251 (1984) 351. 28 Frick, M.H., Elo. O., Haapa, K.. Heinonen. O.P., Heinsalmi. P., Helo. P., Huttonen, J.K., Kaitaniemi, P.. Koskinen, P., Manninen, V., Mlenpla, H., Malkonen, M., Manttari. M.. Norola. S., Pastemack, A., Pikkarainen, J., Romo, M.. Sjoblom, T. and N&kill, E.A., Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia, N. Engl. J. Med., 317 (1987) 1237.

Effect of lovastatin on hemorheology in type II hyperlipoproteinemia.

To assess the effect of lovastatin on blood rheology, the hemorheological determinants fibrinogen, red cell aggregation, plasma viscosity, hematocrit ...
597KB Sizes 0 Downloads 0 Views